Radiation therapy for malignant astrocytomas in adults

Radiotherapy and Oncology, 27 (1993) 181-191

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© 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0167-8140/93/$06.00 RADION 01162

Review Article

Radiation therapy for malignant astrocytomas in adults Frangoise

M o r n e x a, H a l a N a y e l a a n d L u c T a i l l a n d i e r b

aD~partement de Radioth~rapie, Centre L~on B~rard, Lyon and bService de Neurologie, Hopital St Julien, Centre Hospitalier Universitaire, Nancy, France

(Received 9 March 1992; revision received 27 January 1993; accepted 5 February 1993) Key words: High grade astrocytoma; Radiation therapy; Brachytherapy; Chemotherapy; Prognostic factors

Summary High grade (or malignant) astrocytomas remain a formidable therapeutic challenge. The main prognostic factors are patient age, patient performance status, tumor grade, the extent of surgical resection and the presence of fits. These factors could help to identify different groups of patients and should be an advantage in deciding on treatment strategies. Modern imaging techniques provide a more precise idea of tumor volume. The study of tumor recurrence shows that they occur in the immediate vicinity of the primary site. Surgery aside, radiotherapy remains the most important treatment modality. Currently, its standards concerning optimal dose and target volume appear to be accepted overall. There is no doubt that a dose-response relation exists; however, doses exceeding 60 Gy increase morbidity. Therefore 60 Gy is the dose most often cited in the literature. Furthermore, as whole brain irradiation does not decrease the risk of recurrence, a focal irradiation including a defined mean volume is generally used today. Radiosensitizers and heavy particles have not fulfilled their initial promise. Brachytherapy remains an interesting alternative for a limited number of patients. Nevertheless, it seems to increase recurrence at a distance from the primary site and to lead to severe focal lesions. Interstitial thermoradiotherapy may minimize local doses and thus help avoid serious local necrosis. Amongst the other therapeutic alternatives, intravenous chemotherapy using nitrosoureas provides a certain but modest benefit. Other administration modalities are currently undergoing evaluation. These include intra-arterial chemotherapy or high dose chemotherapy with autobone marrow transplantation. The interest of this latter is concerned mainly with anaplastic astrocytomas. Finally, among the future alternatives, gene therapy appears to hold the most promise. Intensive therapies, combined modality treatments, with the recent help of biological innovations, should be proposed to favorable groups of patients.

Introduction The large majority of primary CNS neoplasms are unifocal and hence an effective local therapy might be expected to be curative. However, high grade (or malignant) gliomas (more precisely astrocytomas) of the brain are an intriguing but frustrating tumor for radiation oncologists. These tumors tend to be deeply infiltrating and because of their proximity to critical areas of the brain, total surgical excisionjs exceedingly rare. Radiation directed to the tumor and surrounding area, upon initial diagnosis, unequivocally prolongs survival. The Brain T u m o r Study G r o u p clinical trial (BTSG 69-01) was the first recognized study to show that postoperative radiation therapy significantly increased median survival time in patients with high grade gliomas,

when compared with neurosurgical treatment alone [98]. More recently, as noted by Kolker et al. [60], postoperative photon radiation has been shown to improve survival, provided that doses approaching the tolerance of normal brain tissue are given. Nevertheless, tumor regrowth almost invariably occurs and ultimately leads to patient death. Therefore, the prognosis for these patients remains poor with a median survival time of less than 1 year [14,99]. The purpose of this work is to review the different treatment modalities currently available in malignant astrocytomas, which include anaplastic astrocytomas and glioblastoma multiforme [31, with particular attention to radiotherapy parameters, as well as morbidity, the others treatment modalities and the potential future treatments.

Correspondence to: F. Mornex, D6partement de Radioth6rapie, Centre Leon B6rard, 69008 Lyon, France.

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Prognostic factors The results of treatment of patients with malignant astrocytomas are poor. This has led to some expression of the view that it is unjustified to treat patients with grade malignant astrocytomas once the diagnosis is established. However, the identification of groups of patients with favorable prognostic factors should be an advantage in deciding on treatment strategies. Several groups have described analyses on the influence of prognostic variables in their studies [14,98,99]. In these studies, important factors which have been identified generally include age of patient, performance status, duration of symptoms, extent of neurosurgery and tumor grade. As far as tumor grade is concerned, radiation therapy should not be undertaken without surgical intervention yielding at least enough biopsy material for histopathological diagnosis and grading of the tumor. For grade III anaplastic gliomas, the results of treatment by the combined modality appear to be changing and encouraging survival figures are being recorded. On the contrary, in spite of recent developments in neurooncology, multimodal treatment has not yet produced any long-term significant improvement in the survival of patients with grade IV anaplastic astrocytomas [55]. The 2-year survival rates in different studies for patients with grade III and grade IV anaplastic astrocytomas are 20-45% and 4-10%, respectively. In at least two studies, 18% and 19% 5-year survival rates were reported for grade III anaplastic astrocytomas, whereas the survival was 0% for grade IV astrocytomas [87]. However, it should be noted that in some randomized European studies [5,96], the effect of tumor grade on patient survival did not differ significantly. These results might, in fact, be influenced by Kernohan's grading which was most often referred to in these studies. This grading system mainly defines two groups of patients (grades I-II and Ill-IV). Daumas-Duport, on the other hand, suggests a grading system which offers the advantage of being simple and reproducible and which, furthermore, individualizes a prognosis specific to grade III patients

[18]. The prognostic factors influencing survival have been well studied by a report of the Medical Research Council Brain Tumour Working Party (MRC BTWP) [69]. In this multivariate study, the most important prognostic factors include performance status, age, extent of surgical resection and length of history of fits. These four factors were the only ones which appeared to be independently related to survival. These results are in general agreement with previous studies, all of which confirm the importance of age and performance status, measured on various scales, as prognostic factors. Evidence concerning extent of neurosurgery is conflicting, but it seems to be an important prognostic factor in many studies, as well as in this report. The length of his-

tory of fits, in itself, does not appear to have been studied elsewhere, although presence or absence of fits and duration of symptoms have. A possible explanation of the relationship of symptoms of fits to length of survival is that they lead to earlier detection of the tumor and hence a longer period between detection and death. Surprisingly, the importance of tumor grade is discussed and histology is not considered, in this study, as a prognostic factor. However, the histological classification refers to Kernohan criteria. The DaumasDuport grading system might have changed the results. As a result of this study, a prognostic index was developed in which patients were classified into six groups whose 2-year survival rate was 1-32%. The value of this index was confirmed during a prospective randomized study which compared two radiotherapy doses [7]. The use of this index in association with the grading system proposed by Daumas-Duport should, on the one hand, allow one to better select the patients in the different studies and, on the other hand, should allow a more rigorous comparison of results of different studies. The group with better prognostic factors may be selected for studies with innovative external therapy combined with brachytherapy, stereotactic dynamic boost radiotherapy, chemotherapy, or any such intervention requiring intensive multimodal interaction [55,71]. In addition, this prognostic index could be used to gain some broad indication of the likely course of the disease for an individual patient. It may be of some help in patient counselling. Knowledge of prognostic factors should also be utilized to interpret treatment results, especially in uncontrolled trials. Finally, among the non-clinical prognostic factors, the in vitro and, especially, in vivo study of cell kinetics developed since the advent of monoclonal antibodies directed against iododeoxyuridine (IUdR) and bromodeoxyuridine (BUdR) (two nucleotide analogues) seem promising [50,51]. This technique affords rapid determination of a quantitative or semiquantitative labeling index which reflects the percentage of cells synthesizing DNA. For some authors, a high labeling index for malignant gliomas is statistically linked to a shorter delay of recurrence as well as a shorter survival rate. A possible future application of the technique of tumor cell kinetics might be the adaptation of more or less specific treatment modalities for different tumors. The need to record prognostic factors and to refine treatment comparisons, particularly in phase II trials but also in other studies with small numbers of patients should therefore be emphasized. External beam radiation

Volume of irradiation The question of the optimal volume for treatment of

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malignant gliomas remains a subject of debate. Some investigators favor partial brain irradiation, whereas others, due to the inability to determine microscopic tumor extensions, favor whole brain irradiation. Salazar and Rubin, reporting the autopsy findings of 43 patients with glioblastoma multiforme who died shortly after the establishment of the diagnosis, found that over 80% of all glioblastomas spread either by contiguity (anteroposterior direction or crossing-over to the opposite hemisphere) or by spinal seeding (infratentorial tumors). The authors recommend a whole brain irradiation with generous boosting fields. Furthermore, craniospinal irradiation is recommended in selected cases [80]. Recently, delineation of tumor volume has become more precise with modern diagnostic techniques. However, even with the best currently available CT and MR imaging, direct identification of microscopic margins remains impossible [87]. Hochberg and Pruitt [46] found that CT scans, performed within 2 months of death, defined tumor extension within 2 cm in 80% of patients. Only 1 of 35 autopsies showed microscopic infiltration more than 2 cm beyond the margin indicated by CT scan. Furthermore, as demonstrated by serial CT scans, 90% of recurrences were within 2 cm of the primary site. Urtasun et al. [95], with a 30% autopsy rate, found that all recurrences were within their partial brain target volumes. Recently, Massey and Wallner [68] studied CT scans of 12 patients who underwent resection of recurrent malignant astrocytomas and who had a radiographically documented second tumor recurrence. Eight of 12 second recurrences were no more than 2 cm from the contrast-enhancing margin of the first recurrence. The remaining four patients had tumor recurrence within 2.2, 4.6, 5.1 and 6.9 cm of the enhancing margin of the first tumor recurrence. Kelly et al. [57], correlated CT and MR images with 195 stereotactic biopsies in 40 patients with various histologic types of CNS tumors. It was noted that the biopsies from the isodense CT regions beyond the zone of low attenuation occasionally contained tumor cells. It was unclear if these cells were capable of growth or malignant transformation. The authors concluded that (a) the enhanced area as seen on a CT scan most frequently represented tumor without parenchyma, (b) the area of hypodensity corresponded to parenchyma, either infiltrated by tumor cells or edema and (c) isolated tumor cells tended to infiltrate at least the volume indicated by T2 weighted MR images. With regard to multicentricity, Hochberg and Pruitt [46], found multiple lesions in 4-6% of patients, but in each case the additional lesion had been identified on the CT scan. Choucair et al. [15] reviewed 1047 patients with supratentorial glioblastoma multiforme or anaplastic gliomas treated at UCSF from 1976 to 1985. Multiple lesions were found in 1.1% of these patients at the time of presentation. Four percent of the

glioblastomas and 8.6% of the anaplastic gliomas subsequently developed a new hemispheric lesion; in 1-2% of patients these were accompanied by spinal metastases. Thus, as in the Hochberg and Pruitt study [46], 90% or more recurred only at the original tumor site. What has been the clinical experience with limited versus whole brain irradiation? Using limited volume radiotherapy, a median survival time of 10 months for glioblastoma multiforme was reported, a survival time comparable to that obtained with whole brain radiotherapy in the BTSG and Radiation Therapy Oncology Group/Eastern Cooperation Oncology Group (RTOG/ECOG) trials [76,79,86]: in small (34 patients) randomized trials, no compromise was found in results when limited field radiotherapy was compared with whole brain irradiation. Similarly, the clinical trials reported by Bleehen et al. [7], Urtasun et al. [95] and the MRC working party [72] (who used volumes of about two-third of the brain) reported survival data comparable to those reported by other study groups using whole brain radiation [14,33,99,100]. The Brain Tumor Cooperative Group (BTCG) randomized trial, that included 571 patients with a supratentorial malignant glioma, showed that giving between one-quarter and one-third of the radiotherapy (17.2 Gy out of a total 60.2 Gy) by a cone down boost was as effective as giving whole brain (60.2 Gy) irradiation [32]. Generally, the target volume is considered to be a mean volume which should include at least 3 cm around the peritumoral hypodense edema evidenced by CT scan and at least 2 cm beyond the pathological peritumoral signal indicated by magnetic resonance imaging (MRI). This represents a compromise subject to modification when more effective primary therapy is available, or when more precise diagnostic means are at hand [87].

Dose of radiation The optimal dose for conventional fractionated radiotherapy of a malignant glioma has been controversial. Salazar et al. [90] had previously concluded from a retrospective study that not only was radiation therapy beneficial, but that there appeared to be a radiation dose-response in this group of tumors and recommended that they be treated to at least 70 Gy. In 1979, the same study group [81] reported the results of a clinical trial examining high dose (60 Gy) and very high dose (75 Gy) radiation therapy for malignant gliomas, compared with lower doses (50 Gy). The differences in median survival were significant between the extremes, but not between consecutive dose groups and these differences were only maintained for up to 2 years from the initiation of treatment. The authors concluded that high radiation doses were well tolerated but did not seem to affect total survival of patients nor did they seem capable of sterilizing the tumors. The BTSG retrospectively review-

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ed data from 621 patients entered into randomized trials between 1966 and 1975 [101]. These patients were divided into groups with median doses of 50, 55 and 60 Gy. Although these trials were not designed to evaluate optimal dose, the significant prognostic variables were well balanced between the radiation dose groups. The median survival time was 28 weeks, 36 and 42 weeks, respectively. The difference in survival between doses of 50 and 60 Gy was significant (p = 0.004). Chang et al. [14], reported the results of a randomized RTOG/ECOG study in which no significant difference could be demonstrated between patients receiving 60 Gy versus 70 Gy to the tumor bed. More recently, Miller et al. [70], in their study on 82 patients with high grade gliomas using univariate and multivariate analysis, showed an apparent statistically significant improvement in survival with increasing total radiation dose to the tumor; however, no additional benefit could be demonstrated for doses over 60 Gy. A prospective randomized study for high grade malignant astrocytomas was carried out by the MRC BTWP. A total of 474 patients were included. The first group of patients received 45 Gy in 20 fractions of 2.25 Gy, 5 days a week over 5 weeks on a volume including the tumor and its periphery. The second group received 40 Gy on an identical volume (20 fractions of 2 Gy, 5 days a week over 4 weeks), immediately followed by a complement of 20 Gy, in 10 fractions over 2 weeks, on the tumor volume with a 1-cm margin. A statistically significant increase in the median survival rate was seen for the 60 Gy group (9 months for the 45 Gy group, 12 months for the 60 Gy group). The gain in survival was seen in patients with a poor initial prognostic index as well as in those whose index was more favorable [6]. The major obstacle to the delivery of radiation doses higher than 60 Gy has been normal brain tissue tolerance, particularly late radiation damage. Late damage is related not only to the total dose of radiation and dose per fraction, but also to the volume of normal brain irradiation. In an effort to take advantage of the anticipated gain in CNS tolerance from increasing the number of individual radiation fractions [88], hyperfractionated radiotherapy has been investigated. Because of the rapid turnover of at least a portion of malignant glioma cells [50, 51], accelerated radiotherapy has also been studied. Some investigators have combined hyperfractionation and acceleration. Several randomized studies compared the efficacy and morbidity of hyperfractionatedaccelerated treatment for high grade gliomas [28,31,56,76,89]. These studies showed no survival advantage to the altered fractionation. However, the tolerance to the accelerated schedule appeared to be nearly as good as that with conventional schedules. For patients with poor prognostic factors in whom no long survival is to be expected, hypofractionation has been tried. Kramer et al. [61] had demonstrated that the

acute tolerance for brain irradiation, under corticosteroids, to a fraction dose ranging between 3 and 6 Gy was comparable. Constans and Schlienger [16] had suggested a hypofractionation protocol for glioblastoma multiforme in the form of two courses of 18 Gy over three fractions, 3 days apart, separated by 3 to 4 weeks of rest. Fertil and Malaise [26] showed that, using in vitro glioma cell survival curves, the fraction of cells surviving after a single exposure of 2 Gy was high, representing a large initial shoulder. This observation expresses the high radioresistance of glioma cells and suggests using large fraction sizes (more than 2 Gy) in order to overcome the initial shoulder. In this context, hypofractionation schedules, developed using the linear quadratic model, might increase the tumor control rate, when compared with a conventional schedule. However, late effects are expected to be greater with hypofractionation schemes, with unacceptable morbidity such as dementia [19]. Therefore, the value of hypofractionation schedules in the treatment of the malignant glioma is highly questionable. Predictive tests, evaluating the intrinsic radiosensitivity of high grade gliomas, may help in identifying the individual radiosensitivity of patients. In this way, the fraction size could be 'tailored' patient by patient [30]. However, for the group of patients with poor prognosis, one may be justified in using a shorter irradiation scheme to avoid the taxation of prolonged treatment. Patients who are not likely to survive for more than 6 months should not be subjected to a course of treatment lasting some 6 weeks if an alternative is available with a shorter treatment time and yielding similar results [55]. Radiosensitizers

The grim outlook for patients with malignant gliomas is due to the failure to control local disease. Local persistance after radiotherapy has often been attributed, at least in part, to the presence of hypoxic cells. Regions of coagulative necrosis present in glioblastoma multiforme are likely to contain cells that are hypoxic but still viable. Hypoxic cells are up to three times more resistant to radiation than well oxygenated cells. Hence, they require much larger photon doses to produce the same degree of cell kill as do well oxygenated cells. Attempts to offset the effects of hypoxia have included utilization of hyperbaric oxygen during radiation, hypoxic cell radiation sensitizers and high linear energy transfer (LET) radiation such as neutrons [40,74]. There have been many randomized trials [96] using hypoxic cell radiosensitizers (misonidazole, MISO), with variable entry of patients numbers (33-384), radiation schedules (daily, multiple daily, three fractions/week), total radiation dose (39-60 Gy and total MISO dose (11.25-18 g/m2). No trial in a total of 1930 patients has shown any survival advantage for the MISO groups [4].

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The use of perfluorocarbon emulsions, in view of their small particle size (approx. 1/40 of the diameter of a red blood cell), of their ability to carry large amounts of oxygen in a high Po2 environment and of their ability to release this oxygen rapidly when the environmental Po2 is low, was assessed. It appears that perfluorocarbon emulsions, with conjunction of short-term high inspired oxygen tension, could be worthwhile as an adjuvant to radiation therapy, resulting in an increased therapeutic benefit with lack of toxicity [25]. However, results of other investigations are needed to evaluate the potential efficacy of perfluorocarbon emulsions. The pyrimidine analogues, such as BUdR and IUdR, are radiosensitizers that appear to act independently of the oxygen effect. When BUdR is incorporated into DNA prior to irradiation, it increases the radiation effect 2- to 3-fold. A differential effect between tumor and normal cells is possible since the glioma cells are dividing more rapidly than the very slowly dividing endothelial and stroma cells (the non-dividing normal glial cells are not of concern). Furthermore, the blood-brain barrier tends to protect normal brain tissue, at least that which is not immediately adjacent to the tumor [21,92]. The early clinical trials with BUdR or IUdR showed mixed results [49,58,82,83]. Several phase I studies, while establishing the feasibility of continuous intravenous infusion of BUdR, have reported significant dose-limiting skin and bone marrow toxicities and have questioned the optimal method of pyrimidine analogues delivery [52,56]. Recently, Hegarty et al. [42] developed a permanently implantable infusion pump system for safe, continuous intra-arterial internal carotid BUdR delivery. They have shown that intra-arterial BUdR radiosensitization is safe, tolerable and may lead to improved survival. However, these trials are still in progress.

Heavy particle irradiation Heavy particle beams, consisting of neutrons and heavy ions, possess certain biological properties which may achieve greater local control of more radioresistant tumors [40,54]. Compared with X- or gamma rays, these beams cause more dense ionization per unit length of their path in tissues. This is more effective in tumor cell killing and in rendering those cells that may survive less capable of sublethal damage repair [40]. Furthermore, this type of irradiation is also less dependent than photons on tissue oxygen and on the phase of the cell cycle for their effect on tumor cells [8,40]. Treatment of high grade cerebral astrocytomas with fast neutrons has, so far, been uniformally unsuccessful in extending life, compared with photon irradiation. Autopsy study showed that some patients treated by neutron beams did not die from tumor progression, but from CNS toxicity [12,35]. In an effort to increase the therapeutic ratio,

neutron irradiation for brain tumors should be limited to a boost to the more immediate tumor volume defined by CT scan, following initial whole brain or large volume irradiation with photons. However, the results are not yet encouraging [34,60].

Morbidity Despite the important contributions of Holdorff [48], Gilbert and Kagan [29] and Wara [102], acute and late radiation-induced CNS morbidity poses an important problem in spite of better knowledge of biological effects of radiation and the physiopathologic mechanisms of radiation damage. The clinical manifestations of radiation-induced complications vary greatly according to the site of the primary lesion, which usually receives the highest dose of irradiation [44]. It is clinically and pronostically useful to consider CNS reactions to irradiation according to time of appearance. Three neurologic syndromes associated with radiation therapy are important to recognize: (a) acute reactions occuring during or very shortly after radiation therapy. These reactions are becoming of lesser importance thanks to the great improvement in the techniques of irradiation. (b) an early post-irradiation syndrome occuring 1-3 months after the completion of radiation. Acute and early-delayed reactions usually are manifested by increased intracranial pressure or exacerbation of the focal signs and symptoms of the lesion treated. Therefore, a worsening of signs and symptoms must not always be interpreted as treatment failure, but it may be the expression of transient radiation reaction, probably due to edema and/or transient demyelination (no available histologic confirmation). Thus, these symptoms should not result in a premature decision to alter the treatment program. With conventional therapy, these reactions are usually selflimited, but patients may need and benefit from corticosteroids. (c) a progressive lesion beginning several months to several years after irradiation, which probably results from direct injury to the brain and blood vessels [63]. Late-delayed reactions, which can be irreversible and are often progressive, range from narrowing of large vessels to frank necrosis. Such lesions may lead to impaired intellectual functions [63] or even dementia [19]. These neuropsychological troubles are mainly represented by attention and learning difficulties, which may progress to a more subcortical than cortical form of dementia (respect of symbolic and instrumental functions) [103]. Balance troubles and sphincter function as well as an extrapyramidal syndrome have also been reported [20]. Few studies have been undertaken to more precisely analyze these symptoms considered to be anecdotic in the face of tumor prognosis. Laboratory study of cerebrospinal fluid may evidence isolated high protein level. CT scan reveals three principal findings: diffuse cortical atrophy, dilata-

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tion of ventricles and hypodensity of hemispheric white matter. MRI is more sensitive and shows disseminated T2 signal at the level of deep hemispheric white matter [23]. From a therapeutic point of view, one could imagine that ventricles derivation, indicated in the presence of hydrocephalus, might improve balance trouble and sphincter functions as reported following radiation therapy of brain metastases [16]. In certain cases, there is loss of myelin and axons and necrosis of brain tissue. The symptoms appear often suddenly and the condition is almost impossible to differentiate from a recurrence. CT or MRI does not easily differentiate between brain necrosis and recurrent tumor [22]. The incidence of late-delayed reactions is increasing due to the additive toxic effect of chemotherapy [102] used in conjunction with irradiation and also due to the efficacy of current treatment modalities leading to a higher percentage of intermediate and long-term survivors [44]. The frequency of radiation necrosis as a function of dose and fractionation is not well documented. However, no necrosis is to be expected below 50-55 Gy [67,88]. Kramer et al. [61] reviewed the literature from 1937 to 1969 and found only 57 cases of proven brain necrosis from radiation therapy. Moreover, in only 5 of the 57 cases was the total tumor dose below 70 Gy. A thorough analysis of radionecrosis in the brain was made by Sheline et al. [88]. In mathematical models, the importance of the number of fractions (N) is emphasized and the influence of the time factor is smaller [55]. Moreover, the responsibility of large daily radiation fractions is established and new protocols are tailored with small radiation daily fractions. Small radiation fraction size allows one to avoid or minimize this late syndrome [102]. The safe daily fraction size in the treatment of brain tumors was recommended to be 1.8-1.9 or 9-9.5 Gy per week [75]. Finally, the occuring of secondary neoplasia, which fortunately is a rare event, must be mentioned [13]. In 1970, the median survival of patients harboring malignant gliomas using available surgical techniques and undefined radiation therapy was approximately 6 months: the randomized prospective study conducted by the BTCG reported a median survival of 14 weeks with conventional care and 36 weeks with radiotherapy [99]. Prospective clinical trials over the last 20 years have demonstrated that median survival can be improved to a year or more. Newer therapeutic modalities and multimodality approach hold the promise of improving survival further. Therefore, the magnitude of late effects must be taken into consideration; when designing a new radiation protocol, the most important item is the dose per fraction, followed by total dose, volume of irradiation and combined treatments. The aim of any new treatment protocol is not only to lengthen the survival of patients with malignant gliomas, but also to preserve a reasonable quality of life.

Brachytherapy Focal-radiation techniques have increasingly been considered in the treatment of brain tumors, especially malignant astrocytomas, because these tumors often recur locally and whole brain irradiation is limited by the brain tolerance. One important technique is brachytherapy, such as stereotactic implantation of radiation sources in the tumor [54]. One attractive approach to dose escalation without exceeding the normal brain tissue tolerance is the use of low intensity radiation brachytherapy [84]. Several radioactive isotopes have been used for brain tumor brachytherapy. However, in recent years Iodine-125 and Iridium-192 have been most frequently implanted. Iridium-192 (average energy 0.38 MeV, half-life 74 days) is available in the form of wires of 0.3 mm diameter enveloped in a platinum cover sufficient to stop the emitted/~ particles. Iodine-125 (average energy 30 KeV, half-life 60 days) is in the form of seeds 4.5 mm in length and 0.8 mm in diameter. Being an emitter of very low-energy photons, Iodine-125 implants pose no problems of radioprotection and, therefore, it may be left as a permanent implant [241. In most cases, the radioactive sources are afterloaded in a removable catheter that has been inserted into the malignant brain tumor; the central zones of such tumors are often soft in consistency which predispose to source movement unless held in a fairly rigid container. Interstitial implantation of brain tumors is usually done using CT directed stereotactic techniques. CT stereotaxy allows careful treatment planning and superior implant accuracy. Computer programs are available for stereotactic treatment planning, yielding implant coordinates for optimal isodose coverage [74]. Intensive local therapy seems particularly rational in light of increasing evidence that malignant gliomas recur locally rather than diffusely [1,15,46,62]. Therefore, interstitial brachytherapy has been used as a treatment for recurrent malignant gliomas and in primary therapy as adjuvant treatment for boosting the radiation dose to the tumor. Over 60 centers offer interstitial brachytherapy programs for newly diagnosed or recurrent malignant gliomas. Szikla et al. [93] reported, after stereotactic temporary Iridium-192 implantations, either alone or combined with external irradiation, a 5-year survival rate for grade III malignant astrocytomas of 55%. For nine patients with grade IV tumors, the 1- and 2-year survival rates were 44% and 19%, respectively. Reports from other institutions have noted up to a 50% improvement in survival after implantation. However, the overall survival did not exceed 1 year [37-39,73,93]. Interstitial brachytherapy may be changing the natural history of malignant astrocytomas, by increasing the percentage of distant lesions. Choucair [ 15] reports that multiple lesions develop in only 5% of patients with glioblastomas and 8.6% in anaplastic astrocytomas, dur-

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ing conventional radiation and chemotherapy. However, he found second lesions within the CNS in 3.2% of patients who did not undergo brachytherapy and in 11% of those who did. Loeffier et al. [651, analysed the clinical patterns of failure in 53 patients with malignant gliomas who were treated with stereotactic interstitial irradiation, using temporary implants of high activity Iodine-125. The predominant pattern of failure in these 22 patients was in the margins of the implanted volume (8 patients) and distant sites (10 patients) within the CNS (distant ipsilateral or contralateral hemisphere or spinal axis) or extraneural. Thus marginal and distant recurrences accounted for 82% of the relapses. The authors concluded that stereotactic interstitial irradiation has changed the recurrence pattern in patients with malignant gliomas, with true local recurrence no longer being the predominant pattern of failure, as seen with conventional therapy. The main obstacles to the success of brain tumor brachytherapy are the relatively high incidence of focal brain injury and the occurence of tumor regrowth peripheral to the intensely irradiated field. Local tumor hyperthermia could ameliorate these problems by allowing a reduction in the radiation dose required for local tumor control. Heat, at non-lethal temperatures, is known to sensitize cells to radiation. Thermal enhancement of radiation is accentuated when radiation is delivered at low dose rates in the range of those used in conventional interstitial brachytherapy. The most effective current methods of delivering heat to a deep tumor target involve interstitial implanted microwave antennae or localized current field needles. Fewer sources, probably, would be required for effective heating with the microwave system; hence, this would seem to be the method of choice for brain tumor treatment. Since radioactive sources contained in catheters can be implanted into brain tumors using CT stereotactic techniques, it is relatively easy to extend the technique to the implantation of catheters that also hold heating antennae [74]. Recently, Stea et al. [90] have initiated a phase I clinical trial to determine the feasibility, tolerance and toxicity of interstitial thermoradiotherapy using thermally regulated ferromagnetic implants, afterloaded into stereotactically placed plastic catheters, in the treatment of high grade supratentorial brain gliomas. Among the 19 heat treatments attempted, there have been four minor acute toxicities, medically manageable and one major complication resulting in the demise of a patient. The results of interstitial thermoradiotherapy in the treatment of malignant gliomas are encouraging. However, its value is not yet established and, moreover, its morbidity is not yet very well assessed. Therefore, the application of interstitial thermoradiotherapy should be restricted to clinical trials in highly specialized centers. Finally, in selected cases, non-invasive stereotactic radiosurgical methods are available to provide focal irradiation: the modified linear accelerator with stereotac-

tic guidance [43], the multiple-source cobalt irradiator, or 'gamma-knife' [66] and the proton beam, which uses the Bragg-peak effect to deliver radiation at a distance from the source [59]. These techniques should allow the use of radiation as an ablative tool.

Chemotherapy Controlled clinical trials have demonstrated the efficacy of a number of drugs when combined with irradiation, as adjuvant therapy, in the treatment of malignant gliomas. However, no single drug or drug combination was found statistically superior to nitrosoureas [64], which by virtue of their lipid solubility are able to penetrate the blood-brain barrier. Since they are active against both proliferating and non-proliferating tumor cells, they would be expected to be particularly effective against gliomas because of the low growth fraction of these tumors [8]. However, while nitrosourea agents undoubtedly cause tumor regression and promote clinical improvement in some patients with recurrent gliomas [45,97,101], they appear of little value as adjuvants in the primary treatment of high grade astrocytomas. So far, no consistent and significant improvement has been demonstrated when they are combined with radiation therapy [10,14,45,101]. However, Stenning et al. [911, in a literature search, identified eight studies reported since 1975 in which chemotherapy was by a single agent nitrosourea (CCNU, BCNU, or MeCCNU) and in which survival rates to 24 months were stated. The chemotherapy and radiotherapy regimens did not differ greatly. The overall survival differences on analysis at 12 and 24 months were statistically significant. It was 9% better in the nitrosourea patients at 12 months (p = 0.002) and 3.5% at 24 months (p = 0.046). Bleehen [5] concluded that, in spite of the limitations of such an overview, it has confirmed the value of adjuvant nitrosoureas chemotherapy. In an attempt to combine the effect of nitrosoureas with other effective drugs, Chang et al. [14] studied BCNU and multiagent chemotherapy (MeCCNU and DTIC), as adjuvant therapy to control irradiation. The combination chemotherapy was more toxic than BCNU alone. Other combinations (Procarbazine, CCNU, Vincristine) produced longer survival and time to tumor progression than BCNU, although the difference was statistically significant only for anaplastic astrocytomas [64]. Recently Fine et al. [27] have examined all large prospective, randomized chemotherapeutic trials of malignant gliomas conducted over the past 10 years. They found a consistent beneficial effect for chemotherapy (54% versus 44% 12month survival in patients receiving, respectively, radiation therapy and chemotherapy versus radiation therapy alone). The data suggest that patients with anaplastic astrocytomas certainly benefit from adjuvant chemotherapy. Less benefit is observed in patients with glioblastoma multiforme. These data must be confirmed.

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As the experimental tumor models show a steep doseresponse curve with the nitrosoureas, high doses of BCNU followed by autologous bone marrow transplantation, as part of a multimodality primary treatment, applied after surgical excision and before radiotherapy was attempted in cases of recurrent or primary malignant gliomas [2,11,53,77]. These trials showed that this new approach appears to significantly improve survival, particularly for anaplastic astrocytomas [71]. Intra-arterial chemotherapy with or without crossing the blood-brain barrier has been used since the 1980s [47]. It offers intratumoral concentrations 10-50 times higher than those obtained by the i.v. infusion. Extraneurological toxicity is limited. Neurological toxicity involves impaired ocular function (10-15% of cases) when a subophthalmic route is used and an encephalic impairment (15-30% of cases) symptomatic or non-symptomatic (leuko-encephalopathy) when a supraophthalmic route is used. The rate of response is of 40% without a clearcut incidence on survival [851. Overall, chemotherapy appears to provide a certain, albeit modest, gain in the survival of patients presenting with high grade astrocytomas. This gain appears to be comparable to that afforded by increasing radiotherapy doses from 45 to 60 Gy, i.e. 2-3 months of median survival time. Nevertheless, the heterogeneity of the different studies concerning patients (tumor histology and prognostic factors), drugs and dosages does not readily lend itself to precise and objective analysis of the effective contribution of chemotherapy. To ensure valid evaluation, large-scale prospective randomized studies are called for.

Future aspects Monoclonal antibodies immuno toxins )

(radioimmunotherapy

and

A recent hope is that monoclonal antibodies (MAbs) directed against tumor-specific antigens can be used to diagnose and treat malignant gliomas. Many investigative studies involving the targeting of radiolabeled MAbs in human tumors have demonstrated the unique specificity of tumor cells over normal cells. While some MAbs by themselves have shown direct in vivo tumor cell killing, by immunoreactive mechanisms, the therapeutic responses have recently been increased by the chemical attachment of radionuclides directly to MAbs. It has been shown that significant nuclear chromosomal damage can be caused in tissue culture of human colorectal cancer cells and this damage appears to be specific to the particular MAb and the radiolabel employed [104]. Recently, Brady et al. [9] have treated 25 patients presenting with a malignant astrocytoma by surgical resection and definitive radiation therapy, followed by intravenous or intra-arterial administration

of Iodine-125 labeled monoclonal antibody-425, which binds specifically to human epidermal growth factor (EGFr). As EGFr has been shown to be largely expressed on human glioma cells and not in appreciable amounts (if any) on normal brain cells [94], this MAb could be internalized and translocated into the nucleus and thus will irradiate the tumor cell from within. The administration of the radiolabeled antibody was performed in most cases 4-6 weeks following completion of the primary surgery and radiation therapy. No significant life-threatening toxicities were observed during this radioimmunotherapy trial. At 1 year, 60% of the patients with anaplastic astrocytomas or glioblastoma multiforme were alive with a median survival of 16.5 months. The efficacy of EGFr has been proven in recurrent and primary cases of malignant gliomas; however, a prospective randomized trial comparing results of conventional surgery and radiation therapy alone versus with MAbs deserves to be promoted. Similarly, the cytotoxic activity of immunotoxins has been evaluated. Glioblastoma multiforme has been shown to express high numbers of Transferrin Receptor (TR), which could be a suitable target for TransferrinToxin therapy, monoclonal antibodies raised against these receptors being linked to an immunotoxin. The in vitro cytotoxicity of Transferrin-Toxin conjugates is high and agents could even enhance immunotoxin entry into the cytosol. Future directions will determine the in vivo efficacy of these conjugates [41]. Gene transfer with retroviral vector producer cells

Among the more recent therapeutic advances, gene therapy appears to be the most intellectually seductive. Moreover it may be the only therapeutic alternative allowing one to contemplate such tumors from a curative point of view. Culver et al. [17] report a study concerning a murine model of malignant brain tumor. At first the authors fabricated a recombinant retrovirus containing the thymidine kinase gene of Herpes Simplex Virus. Following implantation of tumor tissue in the rat cerebral hemisphere, murine fibroblasts capable of producing the Herpes Simplex thymidine kinase were stereotaxically injected. On Day 5, the animals were treated by ganciclovir (thymidine analogue). Complete macroscopic regression was observed in 11 of 14 animals. The human clinical trials should soon be under way. Other therapies

Several other therapeutic alternatives are under consideration, which need precise evaluation before being used. Among them, a future neurochirurgical progress seems to be represented by the research of a more precise delimitation of the resection margin of malig-

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nant astrocytomas. It seems that survival could be improved with a more extensive surgical resection. However, most of these tumors do not have a distinct boundary, making complete resection difficult or impossible. A visual detection of neoplastic tissue in intracranial tumors is now possible: in a series of intracerebral glioma implanted rats, a fluorescent dye (phthalocyanine) was injected intravenously 24 h before tumor resection. During neurosurgery procedure, a laser-induced fluorescence spectroscopy was able to delineate tumor margins. This in vivo use of laser-induced fluorescence resulted in a better tumor excision and better survival in animals, when compared with a control group that underwent classical visual resection. This study shows that intraoperative laser-induced measurement is an effective means of delineating tumor margin and has potential clinical applications in terms of identification of tumor margins, as well as localization of subcortical tumor during open operation and confirmation of target in stereotactic tumor biopsies [78]. Another hope is represented by a new route of chemotherapy administration. Besides the intra-arterial chemotherapy administration [47], in situ treatment is currently being evaluated, with the use of surgically implanted biodegradable polymers [36]: in an effort to decrease local recurrences of malignant astrocytomas, recent studies have focused on increasing the delivery of chemotherapy to tumor-bearing regions. Implanted biodegradable polyanhydrides that release chemotherapeutic agents in an active form for prolonged periods of time could improve local control. The biocompatibility of these polymers in brain tissue has been demonstrated in animal models, as their ability to release biologically active nitrosoureas for extended periods of time. Thus, high local concentrations of cytotoxic agents would be delivered to tumor and adjacent tissues, systemic toxicity of these agents would be minimized and the problem of the blood-brain barrier would be eliminated. The potential therapeutic benefit of this system will be the next step of this study.

Conclusion Conventional radiotherapy of malignant astrocytomas is currently well codified: a dose of 60 Gy or equivalent, delivered on a precisely defined target volume. The effective contribution of radiosensitizers does not appear to be sufficiently convincing. The same holds true for heavy particles. Major radiation-related morbidity such as radionecrosis is less of a problem today thanks to improved irradiation techniques. The same cannot be said, however, for minor radiationinduced morbidity. These are often associated with neuropsychological problems, impaired balance function and even extrapyramidal syndrome. Interstitial brachytherapy remains limited to a restricted number of

patients. Even though it is only moderately effective, chemotherapy now has its rightful place in the management of malignant brain tumors. Radioimmunotherapy also seems to hold promise. Finally, the fascinating concept of gene therapy might yet hold the key to the curative management of these neoplasms whose prognosis remains black. The need to record prognostic factors and to refine treatment comparisons, particularly in phase II trials but also in other studies with small numbers of patients should therefore be emphasized. These factors could help to identify different groups of patients and should be an advantage in deciding on treatment strategies. Intensive therapies, combinedmodality treatments, with the recent help of biological innovations, should be proposed to favorable groups of patients.

Acknowledgments The authors are most grateful to Dr. Joseph R. Castro and to Dr. William Canada for help in preparing the manuscript.

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